Cyclodextrins are cyclic oligosaccharides. The most common cyclodextrins are .alpha.-cyclodextrin, which is composed of a ring of six glucose residues, .beta.-cyclodextrin, which is composed of a ring of seven glucose residues, and .gamma.-cyclodextrin, which is composed of a ring of eight glucose units. The inside cavity of a cyclodextrin is lipophilic, while the outside of the cyclodextrin is hydrophilic; this combination of properties has led to widespread study of the natural cyclodextrins, particularly in connection with pharmaceuticals, and many inclusion complexes have been reported. .beta.-Cyclodextrin has been of special interest because of its cavity size, but its relatively low aqueous solubility has limited its use in the pharmaceutical field.
Attempts to modify the properties of the natural cyclodextrins have resulted in the development of heptakis (2,6-di-O-methyl)-.beta.-cyclodextrin, heptakis (2,3,6-tri-O-methyl)-.beta.-cyclodextrin, hydroxypropyl-.beta.-cyclodextrin, .beta.-cyclodextrin-epichlorohydrin polymer and others. For a comprehensive review of cyclodextrins and their use in pharmaceutical research, see Pitha et al, in Controlled Drug Delivery, ed. S. D. Bruck, Vol. I, CRC Press, Boca Raton, Fla., pp. 125-148 (1983). For an even more recent overview, see Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), pp. 1-40 (1987); and Pagington, Chemistry in Britain, May 1987, pp. 455-458.
Inclusion complexes of .alpha.-, .beta.- or .gamma.-cyclodextrin or their mixtures with a variety of drugs have been described by numerous parties and various advantages have been attributed to the complexes. These descriptions include the following:
__________________________________________________________________________ U.S. ACTIVE INVENTOR PAT. NO. INGREDIENT USE ADVANTAGE __________________________________________________________________________ Noda et al 4,024,223 menthol &/or antiphlogistic, reduced unpleasant methyl analgesic odor, increased salicylate wet packing effect Szejtli et al 4,228,160 indomethacin anti-inflam- reduced ulcerative matory, pro- effect tective during pregnancy Hayashi et al 4,232,009 .omega.-halo-PGI.sub.2 hypotensive, increased stability analogs uterine con- traction stimulating, blood platelet aggregation inhibition Matsumoto et al 4,351,846 3-hydroxy- and uterine contac- increased stability 3-oxo- tion stimulating prostaglandin analogs Yamahira et al 4,352,793 bencyclane anticonvulsant, increased stability fumarate vasodilative at strong acid pH, faster gastric emptying, higher blood concentrations, less irratation, improved hemolytic activity Lipari 4,383,992 steroids-- hormonal improved water corticosteroids, solubility, increased androgens, therapeutic response anabolic in eye steroids, estrogens, proestagens Nicolau 4,407,795 p-hexadecyl- antiathero- enhanced aminobenzoic sclerotic bioavailability acid sodium salt Tuttle.sup.1 4,424,209 3,4-diisobutyr- cardiac yloxy-N-[3-(4- contractility isobutyryloxy- agent phenyl)-1- methyl-n- propyl]-.beta.- phenethylamine Tuttle 4,425,336 3,4-dihydroxy- cardiac capable of oral N-[3-(4-hydroxy- contractility administration phenyl)-1- agent methyl-n- propyl]-.beta.- phenethylamine Wagu et al 4,438,106 EPA and DHA deodorized, (fatty acids) storage stable Masuda et al.sup.2 4,474,811 2-(2-fluoro-4- anti- reduced eye biphenylyl)pro- inflammatory irritation, pionic acid ophthalmic higher concen- or salt trations, no side effects, highly, soluble, long stability, excellent pharmacological effects Shinoda et al 4,478,995 acid addition anti-ulcer excellent water salt of (2'- solubility, good benzoyloxycar- absorption in diges- bonyl)phenyl tive, tract, good trans-4-guani- anti-ulcer activity dinomethylcyclo- hexanecarboxylate Hayashi et al 4,479,944 PGI.sub.2 analog for treatment of stabilization against artereosclerosis, decomposition cardiac failure or thrombosis Hayashi et al 4,479,966 6,9-methano- for hypertension, increased stability PGI.sub.2 analogs cerebral throm- bosis and the like Harada et al 4,497,803 lankacidin- antibiotic for enhanced water group antibiotic swine dysentery solubility and stability, increased rate and amount of absorption Masuda 4,499,085 prostaglandin treating anoxia analog of brain cells Szejtli et al 4,518,588 phendiline, i.e. coronary dilator improved water solu- N-(1-phenyl- calcium bility, accelerated ethyl)-3,3- antagonist and increased in diphenylpro- vivo resorption pylamine or its & dissolution at pH/ hydrochloride temperature of gastric acid Szejtli et al 4,524,068 piperonyl synergizes easily handled butoxide pesticidal effect crystalline solid; of known insecti- improved water solu- cides and fungi- bility, increased cides absorption & velocity of penetration through biological membranes Jones 4,555,504 a cardiac cardiac effect high aqueous solu- glycoside bility, apparently better bioavail- ability Uekama et al.sup.3 4,565,807 piprofen anti-inflam- improved stability matory, to oxidation, analgesic, freedom from bitter antipyretic taste, less irrita- ting Ueda et al 4,575,548 2-nitroxymethyl- for vascular non-volatile power 6-chloropyridine disorders vs. volatile oil Ohwaki et al.sup.4 4,598,070 tripamide anti-hyper- improved solubility tensive Chiesi et al 4,603,123 piroxicam, i.e. anti-inflam- 4-hydroxy-2- matory, analgesic methyl-N-2- pyridyl-2H-1,2- benzothiazine-3- carboxamide-1,1- dioxide Hasegawa et al 4,608,366 mobenzoxamine, antiemetic, storage stability, i.e. 1-[2-(4- antispasmodic better absorption methoxybenzhy- through digestive dryloxy)ethyl]- tract 4-[3-(4-fluoro- benzoyl)propyl]- piperazine Hirai et al.sup.2 4,659,696 polypeptide improving drug absorption by non- oral and non- injection routes Szejtli et al 4,623,641 PGI.sub.2 methyl anti-ulcer improved storage ester stability Ninger et al 4,663,316 unsaturated antibiotic, enhanced stability phosphorus- antifungal, against oxidation containing antitumor antibiotics, including phosphotrienin Fukazawa et al 4,675,395 hinokitiol bactericidal, improved water bacteriostatic solubility, less odor __________________________________________________________________________ .sup.1 Tuttle also describes use of 2,6di-O-methyl-.beta.-cyclodextrin an 2,3,6tri-O-methyl-.beta.-cyclodextrin to form the inclusion complex. .sup.2 This may not be an inclusion complex, but simply a physical mixture. .sup.3 This is a mixture and/or an inclusion compound. .sup.4 The inventors also mention prior known solubility improvements of cyclodextrin inclusions of barbituric acid derivatives, mefenamic acid, indomethacin and chloramphenicol. .sup.5 The inventors refer to this as an "occlusion" compound.
Inclusion complexes of 2,6-di-O-methyl-.beta.-cyclodextrin with dibenzo[bd]pyran derivatives and salts having analgesic, antemetic and narcosis-potentiating activities have been described in Nogradi et al U.S. Pat. No. 4,599,327; increased water solubility and thus improved biological activity have been claimed for the complexes. A review of the pharmaceutical applications of such methylated cyclodextrins has been published by Uekama, Pharm. Int., March 1985, 61-65; see also Pitha, Journal of Inclusion Phenomena 2, 477-485 (1984).
Cyclodextrin polymer has been reported by Fenyvesi et al, Chem. Pharm. Bull. 32 (2), 665-669 (1984) to improve the dissolution of furosemide. Improvements in the dissolution and absorption of phenytoin using a water-soluble .beta.-cyclodextrin epichlorohydrin polymer have been described by Uekama et al, International Journal of Pharmaceutics, 23, 35-42 (1985).
Hydroxypropyl-.beta.-cyclodextrin (HPCD) and its preparation by propylene oxide addition to .beta.-cyclodextrin were described in Gramera et al U.S. Pat. No. 3,459,731 nearly 20 years ago. Much more recently, Pitha and co-workers have described the improved preparation of this cyclodextrin derivative and its effects on the dissolution of various drug molecules. Pitha U.S. Pat. No. 4,596,795, dated June 24, 1986, describes inclusion complexes of sex hormones, particularly testosterone, progesterone and estradiol, with specific cyclodextrins, preferably hydroxypropyl-.beta.-cyclodextrin and poly-.beta.-cyclodextrin. The complexes enable the sex hormones to be successfully delivered to the systemic circulation via the sublingual or buccal route; the effectiveness of this delivery is believed to be due to "the high dissolution power of hydrophilic derivatives of cyclodextrins, the non-aggregated structure of their complexes with steroids, and their low toxicity and irritancy of mouth tissue". See also Pitha et al, J. Pharm. Sci., Vol. 74, No. 9, September 1985, 987-990, concerning the same and related studies. Pitha et al also describe in the J. Pharm. Sci. article the storage stability of tablets containing a testosterone-hydroxypropyl-.beta.-cyclodextrin complex as well as the lack of toxicity of the cyclodextrin itself.
The improved, optimized preparation and purification of hydroxypropyl-.beta.-cyclodextrin has been recently described by Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986). In the same publication, the authors have described increased water solubility for 32 drugs in concentrated (40 to 50%) aqueous solutions of hydroxypropyl-.beta.-cyclodextrin; improved solubilization of acetamidophen, apomorphine, butylated hydroxytoluene, chlorthalidone, cholecalciferol, dexamethasone, dicumarol, digoxin, diphenylhydantoin, estradiol, estriol, ethinylestradiol-3-methyl ether, ethisterone, furosemide, hydroflumethiazide, indomethacin, iproniazid phosphate, 17-methyltestosterone, nitroglycerin, norethindrone, ouabain, oxprenolol, progesterone, retinal, retinoic acid (all trans and salt forms), retinol, spironolactone, sulpiride, testosterone and theophylline was noted. The authors indicated this to be an extension of their earlier work with hydroxypropyl-.beta.-cyclodextrin, which was previously found effective for oral administration of the sex hormones to humans. Their later work reported in Pitha et al, International Journal of Pharmaceutics, 29, 73-82 (1986), has also been very recently described in Pitha U.S. Pat. No. 4,727,064, dated Feb. 23, 1988. That patent claims a composition containing an amorphous complex of cyclodextrin and a drug, and a method of producing a stabilizing amorphous complex of a drug and a mixture of cyclodextrins comprising (1) dissolving an intrinsically amorphous mixture of cyclodextrin derivatives which are water soluble and capable of forming inclusion complexes with drugs in water; and (2) solubilizing lipophilic drugs into aqueous media to form a solution and form a solubilized drug/cyclodextrin complex.
Uekama et al, CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3 (1), pp. 1-40 (1987), have described the characteristics of various cyclodextrins, including hydroxypropyl-.beta.-cyclodextrin. The authors have presented data showing improved solubilization in water in the presence of 15 mg/mL of HPCD for the drugs carmoful, diazepam, digitoxin, digoxin, flurbiprofen, indomethacin, isosorbide dinitrate, phenytoin, prednisolone, progesterone and testosterone. In a discussion of the metabolism and toxicity of cyclodextrins, Uekama et al have indicated that cyclodextrins at sufficiently high concentrations cause hemolysis, and that the methylated cyclodextrins have higher hemolytic activity than the natural cyclodextrins. Hydroxypropyl-.beta.-cyclodextrin is said to cause hemolysis beginning at 4.5 mM. The authors have further indicated that parenteral administration of large doses of cyclodextrins should be avoided, but that ".gamma.-cyclodextrin and hydroxypropyl-.beta.-cyclodextrin seem to be useful in drug solubilization for injections and liquid preparations used for mucous membranes."
JANSSEN PHARMACEUTICA N.V.'s International Patent Application No. PCT/EP84/00417, published under International Publication No. WO85/02767 on July 4, 1985, has described pharmaceutical compositions comprising inclusion compounds of drugs, which are unstable or only sparingly soluble in water, with partially etherified .beta.-cyclodextrin derivatives having hydroxyalkyl and optionally additional alkyl groups. Among the cyclodextrin derivatives contemplated is hydroxypropyl-.beta.-cyclodextrin, while the drugs include nonsteroidal anti-rheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine, piperazine, imidazole and triazole. Preferred drugs include etomidate, ketoconazole, tubulazole, itraconazole, levocabastine and flunarizine. The pharmaceutical compositions of the invention include oral, parenteral and topical formulations, with 4 to 10% solutions of cyclodextrin derivatives being utilized to solubilize various drugs. Improved solubilities of indomethacin, digitoxin, progesterone, dexamethasone, hydrocortisone and diazepam using 10% HPCD are showna, and an injectable formulation of diazepam in 7% HPCD is specifically described. The relatively low cyclodextrin concentrations used reflect a desire to avoid or minimize the hemolytic effects observed at higher cyclodextrin concentrations.
Carpenter et al, The Journal of Pediatrics, 111, 507-512 (October 1987) describe intravenous infusion of 2-hydroxypropyl-.beta.-cyclodextrin, prepared as a 5% solution in water, to treat severe hypervitaminosis A. It was found that, during infusion, circulating retinyl esters increased transiently, while total vitamin A excreted in the urine was enhanced after infusion. Thus, intravenous infusion of 5% HPCD was found to decrease in vivo levels of the vitamin, presumably by complexing with the vitamin and removing some of the excess from the body.
The delivery of drugs to the brain is often seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall, i.e. the blood-brain barrier or BBB. Site-specific delivery and sustained delivery of drugs to the brain are even more difficult.
A dihydropyridine pyridinine.revreaction.pyridinium salt redox system has recently been successfully applied to delivery to the brain of a number of drugs. Generally speaking, according to this system, a dihydropyridine derivative of a biologically active compound is synthesized, which derivative can enter the CNS through the blood-brain barrier following its systemic administration. Subsequent oxidation of the dihydropyridine species to the corresponding pyridinium salt leads to delivery of the drug to the brain.
Three main approaches have been published thus far for delivering drugs to the brain using this redox system. The first approach involves derivation of selected drugs which contain a pyridinium nucleus as an integral structural component. This approach was first applied to delivering to the brain N-methylpyridinium-2-carbaldoxime chloride (2-PAM), the active nucleus of which constitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Thus, a hydrophilic compound (2-PAM) was made lipoidal (i.e. lipophilic) by making its dihydropyridine form (Pro-2-PAM) to enable its penetration through lipoidal barriers. This simple prodrug approach allowed the compound to get into the brain as well as other organs, but this manipulation did not and could not result in any brain specificity. On the contrary, such approach was delimited to relatively small molecule quaternary pyridinium ring-containing drug species and did not provide the overall ideal result of brain-specific, sustained release of the desired drug, with concomitant rapid elimination from the general circulation, enhanced drug efficacy and decreased toxicity. No "trapping" in the brain of the 2-PAM formed in situ resulted, and obviously no brain-specific, sustained delivery occurred as any consequence thereof: the 2-PAM was eliminated as fast from the brain as it was from the general circulation and other organs. Compare U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al, J. Pharm. Sci, 67, No. 5, 685 (1978). See also Bodor, "Novel Approaches for the Design of Membrane Transport Properties of Drugs", in Design of Biopharmaceutical Properties Through Prodrugs and Analogs, Roche, E. B. (ed.), APhA Academy of Pharmaceutical Sciences, Washington, D.C., 98-135 (1976). Subsequent extension of this first approach to delivering a much larger quaternary salt, berberine, to the brain via its dihydropyridine prodrug form was, however, found to provide site-specific sustained delivery to the brain of that anticancer agent. See Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372.
The second approach for delivering drugs to the brain using the redox system involves the use of a pyridinium carrier chemically linked to a biologically active compound. Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372, outline a scheme for this specific and sustained delivery of drug species to the brain, as depicted in the following Scheme I: ##STR1## According to the scheme in Science, a drug [D] is coupled to a quaternary carrier [QC].sup.+ and the [D-QC].sup.+ which results is then reduced chemically to the lipoidal dihydro form [D-DHC]. After administration of [D-DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH system) to the ideally inactive original [D-DC].sup.+ quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D-QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (k.sub.6 &gt; &gt;k.sub.2). Because of the facile elimination of [D-QC].sup.+ from the general circulation, only minor amounts of drug are released in the body [k.sub.3 &gt;&gt;k.sub.4); [D] will be released primarily in the brain (k.sub.4 &gt;k.sub.2). The overall result ideally will be a brain-specific sustained release of the target drug species. Specifically, Bodor et al worked with phenylethylamine as the drug model. That compound was coupled to nicotinic acid, then quaternized to give compounds of the formula ##STR2## which were subsequently reduced by sodium dithionite to the corresponding compounds of the formula ##STR3## Testing of the N-methyl derivative in vivo supported the criteria set forth in Scheme I. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotinic acid esters and amides and their pyridine ring-substituted derivatives was being studied for delivery of amino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed. Other reports of this work with the redox carrier system have appeared in The Friday Evening Post, Aug. 14, 1981, Health Center Communications, University of Florida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; and Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. More recently, the redox carrier system has been substantially extended in terms of possible carriers and drugs to be delivered. See International Patent Application No. PCT/US83/00725, filed May 12, 1983 and published Nov. 24, 1983 under International Publication No. WO83/03968. Also see Bodor et al, Pharmacology and Therapeutics, Vol. 19, No. 3, pp. 337-386 (1983); and Bodor U.S. Pat. No. 4,540,564, issued Sept. 10, 1985.
The third approach for delivering drugs to the brain using the redox system provides derivatives of centrally acting amines in which a primary, secondary or tertiary amine function has been replaced with a dihydropyridine/pyridinium salt redox system. These brain-specific analogs of centrally acting amines have been recently described in International Patent Application No. PCT/US85/00236, filed Feb. 15, 1985 and published Sept. 12, 1985 under International Publication No. WO85/03937. The dihydropyridine analogs are characterized by the structural formula ##STR4## wherein D is the residue of a centrally acting primary, secondary or tertiary amine, and ##STR5## is a radical of the formula ##STR6## wherein the dotted line in formula (a) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (b) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system; m is zero or one; n is zero, one or two; p is zero, one or two, provided that when p is one or two, each R in formula (b) can be located on either of the two fused rings; q is zero, one, or two, provided that when q is one or two, each R in formula (c) can be located on either of the two fused rings; and each R is independently selected from the group consisting of halo, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio. C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, --CH.dbd.NOR"' wherein R"' is H or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which can be the same or different, are each H or C.sub.1 -C.sub.7 alkyl. These dihydropyridine analogs act as a delivery system for the corresponding biologically active quaternary compounds in vivo. Due to its lipophilic nature, the dihydropyridine analog will distribute throughout the body and has easy access to the brain through the blood-brain barrier. Oxidation in vivo will then provide the quaternary form, which will be "locked" preferentially in the brain. In contra-distinction to the drug-carrier entities described in Bodor U.S. Pat. No. 4,540,564 and related publications, however, there is no readily metabolically cleavable bond between drug and quaternary portions, and the active species delivered is not the original drug from which the dihydro analog was derived, but rather is the quaternary analog itself.
Each of the major dihydropyridine.revreaction.pyridinium redox systems for brain-targeted drug delivery thus has its own unique characteristics but also has properties in common with the other approaches. Common to the various approaches is introduction of a dihydropyridine-type nucleus into the drug molecule, which renders the dihydropyridine-containing drug derivative substantially more lipophilic than the parent drug from which it is derived. The increased lipophilicity enables the derivative to readily penetrate biological membranes, including the blood-brain barrier. Also common to the various approaches is the fact that the "redox" nature of the dihydropyridine-type moiety means that the lipophilic dihydropyridine form is oxidizable in vivo to the hydrophilic, ionic pyridinium salt form, thus locking in the brain either the active drug or its quaternary precursor, depending on which approach is employed.
The dihydropyridine.revreaction.pyridinium salt redox carrier and analog systems have achieved remarkable success in targeting drugs to the brain in laboratory tests. This success is, of course, due in part to the highly lipophilic nature of the dihydropyridine-containing derivatives, which allows brain penetration. At the same time, the increased lipophilicity makes it practically impossible to formulate aqueous solutions of these derivatives for injection; moreover, even when the dihydropyridines are dissolved in organic solvents such as dimethylsulfoxide, they have a propensity for precipitating out of solution upon injection, particularly at higher concentrations, and especially at the injection site or in the lungs. Indeed, even in the absence of noticeable crystallization, it has been found that the redox derivatives frequently display not only the desired concentration in the brain but undesired lung concentrations as well, so that while the brain to blood ratios are at appropriate high levels, the initial lung to brain levels are high as well. Still further, the dihydropyridine-containing derivatives suffer from stability problems, since even in the dry state they are very sensitive to oxidation as well as to water addition. These problems, which must be overcome so that the dihydropyridine .revreaction.pyridinium salt redox systems can be fully commercialized, have been addressed by applicant's copending application Ser. No. 139,755 and are also addressed by the present application. In particular, the present application addresses the problems related to unfavorable concentration/precipitation of the dihydropyridine.revreaction.pyridinium salt redox systems at or near the injection site and/or in the lungs, following parenteral administration, as well as similar problems encountered with other drugs which are insoluble, sparingly soluble and/or unstable in water.